<p>Activin
B, a TGFβ ligand, is associated with liver inflammatory response. We aimed to
investigate whether it modulates liver fibrogenesis. <b> </b>Liver and
serum activin B, along with its analog activin A, were analyzed in patients
with liver fibrosis from different etiologies and in mouse acute liver injury
and liver fibrosis models. Activin B, activin A, or both was immunologically
neutralized in progressive or established carbon tetrachloride-induced mouse
liver fibrosis. The direct effects of activin B and A on hepatocytes,
macrophages, and hepatic stellate cells (HSCs) were evaluated <i>in vitro</i>. In human patients, increased activin B is associated with liver
fibrosis irrespective of the etiologies. In mice, activin B exhibited
persistent elevation in liver and circulation following the onset of liver
injury, whereas activin A displayed transient increases. Neutralizing activin B
largely prevented and remarkably regressed liver fibrosis, which was augmented
by co-neutralizing activin A in mice. Mechanistically, activin B promoted
hepatocyte injury, activated macrophages to release cytokines, and induced a
pro-fibrotic expression profile and septa formation in HSCs, which were
magnified by activin A. Furthermore, activin B and A interdependently activated
the CXCL1/iNOS pathway in macrophages and additively upregulated CTGF
transcript in HSCs <i>in vitro</i>. Consistently, the expression of these genes
was prohibited by neutralizing either one of these two ligands in injured
livers. Activin B potently drives the initiation and progression of
liver fibrogenesis. It additively or interdependently cooperates with activin
A, directly acts on multiple liver cell populations, and induces liver
fibrogenesis.<b> </b>Antagonizing activin B or both activins B and A prevents
and regresses liver fibrosis in mouse CCl<sub>4</sub> model, inspiring the
development of a novel therapy of chronic liver diseases.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8979728 |
| Date | 16 October 2019 |
| Creators | Yan Wang (7022162) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/ACTIVIN_B_PROMOTES_HEPATIC_FIBROGENESIS/8979728 |
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